High-resolution spatial and spatiotemporal modelling of air pollution using fixed site and mobile monitoring in a Canadian city.

The development of high-resolution spatial and spatiotemporal models of air pollutants is essential for exposure science and epidemiological applications. While fixed-site sampling has conventionally provided input data for statistical predictive models, the evolving mobile monitoring method offers improved spatial resolution, ideal for measuring pollutants with high spatial variability such as ultrafine particles (UFP). The Quebec Air Pollution Exposure and Epidemiology (QAPEE) study measured and modelled the spatial and spatiotemporal distributions of understudied pollutants, such as UFPs, black carbon (BC), and brown carbon (BrC), along with fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in Quebec City, Canada. We conducted a combined fixed-site (NO2 and O3) and mobile monitoring (PM2.5, BC, BrC, and UFPs) campaign over 10-months. Mobile monitoring routes were monitored on a weekly basis between 8am-10am and designed using location/allocation modelling. Seasonal fixed-site sampling campaigns captured continuous 24-h measurements over two-week periods. Generalized Additive Models (GAMs), which combined data on pollution concentrations with spatial, temporal, and spatiotemporal predictor variables were used to model and predict concentration surfaces. Annual models for PM2.5, NO2, O3 as well as seven of the smallest size fractions in the UFP range, had high out of sample predictive accuracy (range r2: 0.54-0.86). Varying spatial patterns were observed across UFP size ranges measured as Particle Number Counts (PNC). The monthly spatiotemporal models for PM2.5 (r2 = 0.49), BC (r2 = 0.27), BrC (r2 = 0.29), and PNC (r2 = 0.49) had moderate or moderate-low out of sample predictive accuracy. We conducted a sensitivity analysis and found that the minimum number of 'n visits' (mobile monitoring sessions) required to model annually representative air pollution concentrations was between 24 and 32 visits dependent on the pollutant. This study provides a single source of exposure models for a comprehensive set of air pollutants in Quebec City, Canada. These exposure models will feed into epidemiological research on the health impacts of ambient UFPs and other pollutants

Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice

ObjectiveThe aim of this study was to elucidate whether age plays a role in the expansion or regeneration of beta-cell mass.Research design and methodsWe analyzed the capacity of beta-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration.ResultsYoung mice responded to high-fat diet by increasing beta-cell mass and beta-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in beta-cell mass or beta-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of beta-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and beta-cell proliferation was analyzed to assess the regeneration of beta-cells. We observed a fourfold increase in beta-cell proliferation in young mice after STZ administration, whereas no changes in beta-cell proliferation were observed in older mice. The capacity to expand beta-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of beta-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16(Ink4a)expression in the beta-cells. Young Bmi1(-/-) mice that prematurely upregulate p16(Ink4a)failed to expand beta-cell mass in response to exendin-4, indicating that p16(Ink4a)levels are a critical determinant of beta-cell mass expansion.Conclusionsbeta-Cell proliferation and the capacity of beta-cells to regenerate declines with age and is regulated by the Bmi1/p16(Ink4a)pathway

Associations between ambient air pollution and daily mortality in a cohort of congestive heart failure: Case-crossover and nested case-control analyses using a distributed lag nonlinear model.

BACKGROUND: Persons with congestive heart failure may be at higher risk of the acute effects related to daily fluctuations in ambient air pollution. To meet some of the limitations of previous studies using grouped-analysis, we developed a cohort study of persons with congestive heart failure to estimate whether daily non-accidental mortality were associated with spatially-resolved, daily exposures to ambient nitrogen dioxide (NO2) and ozone (O3), and whether these associations were modified according to a series of indicators potentially reflecting complications or worsening of health. METHODS: We constructed the cohort from the linkage of administrative health databases. Daily exposure was assigned from different methods we developed previously to predict spatially-resolved, time-dependent concentrations of ambient NO2 (all year) and O3 (warm season) at participants' residences. We performed two distinct types of analyses: a case-crossover that contrasts the same person at different times, and a nested case-control that contrasts different persons at similar times. We modelled the effects of air pollution and weather (case-crossover only) on mortality using distributed lag nonlinear models over lags 0 to 3 days. We developed from administrative health data a series of indicators that may reflect the underlying construct of "declining health", and used interactions between these indicators and the cross-basis function for air pollutant to assess potential effect modification. RESULTS: The magnitude of the cumulative as well as the lag-specific estimates of association differed in many instances according to the metric of exposure. Using the back-extrapolation method, which is our preferred exposure model, we found for the case-crossover design a cumulative mean percentage changes (MPC) in daily mortality per interquartile increment in NO2 (8.8 ppb) of 3.0% (95% CI: -0.4, 6.6%) and for O3 (16.5 ppb) 3.5% (95% CI: -4.5, 12.1). For O3 there was strong confounding by weather (unadjusted MPC = 7.1%; 95% CI: 1.7, 12.7%). For the nested case-control approach the cumulative MPC for NO2 in daily mortality was 2.9% (95% CI: -0.9, 6.9%) and for O3 7.3% (95% CI: 3.0, 11.9%). We found evidence of effect modification between daily mortality and cumulative NO2 and O3 according to the prescribed dose of furosemide in the nested case-control analysis, but not in the case-crossover analysis. CONCLUSIONS: Mortality in congestive heart failure was associated with exposure to daily ambient NO2 and O3 predicted from a back-extrapolation method using a land use regression model from dense sampling surveys. The methods used to assess exposure can have considerable influence on the estimated acute health effects of the two air pollutants

Relationship Between Biogenic Amines and Free Amino Acid Contents of Winesand Musts from Alentejo (Portugal)

The concentration of biogenic amines and free amino acids was studied in 102 Portuguese wines and 18 musts from Alentejo demarcated (D.O.C.) regions. Most wines were commercial, except for 38 monovarietals obtained by micro vinification. Musts from the varieties used to produce the latter wines were also studied. Both biogenic amines and free amino acids were analyzed by HPLC using fluorescence detection for their o-phthalaldehyde/fluorenylmethyl chloroformate (OPA/FMOC) derivatives. The most significant amines (average 10.8 mg/L for histamine+tyramine in red, and 7.4 mg/L for white wines) were found to be present at low levels and, although no important relationship between each individual biogenic amine could be obtained, the total amine content depends significantly on the assimilable amino acid content in wine

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes: Interactions With Metformin

ObjectiveWe sought to establish the extent and mechanisms by which sitagliptin and metformin singly and in combination modify islet disease progression in human islet amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes.Research design and methodsHIP rats were treated with sitagliptin, metformin, sitagliptin plus metformin, or no drug as controls for 12 weeks. Fasting blood glucose, insulin sensitivity, and beta-cell mass, function, and turnover were measured in each group.ResultsSitagliptin plus metformin had synergistic effects to preserve beta-cell mass in HIP rats. Metformin more than sitagliptin inhibited beta-cell apoptosis. Metformin enhanced hepatic insulin sensitivity; sitagliptin enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. beta-Cell function was partially preserved by sitagliptin plus metformin. However, sitagliptin treatment was associated with increased pancreatic ductal turnover, ductal metaplasia, and, in one rat, pancreatitis.ConclusionsThe combination of metformin and sitagliptin had synergistic actions to preserve beta-cell mass and function and enhance insulin sensitivity in the HIP rat model of type 2 diabetes. However, adverse actions of sitagliptin treatment on exocrine pancreas raise concerns that require further evaluation

Linagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity

Linagliptin (tradjenta™) is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 inhibition attenuates insulin resistance and improves peripheral glucose utilization in humans. However, the effects of chronic DPP-4 inhibition on insulin sensitivity are not known. The effects of long-term treatment (3–4 weeks) with 3 mg/kg/day or 30 mg/kg/day linagliptin on insulin sensitivity and liver fat content were determined in diet-induced obese C57BL/6 mice. Chow-fed animals served as controls. DPP-4 activity was significantly inhibited (67–89%) by linagliptin (P<0.001). Following an oral glucose tolerance test, blood glucose concentrations (measured as area under the curve) were significantly suppressed after treatment with 3 mg/kg/day (–16.5% to –20.3%; P<0.01) or 30 mg/kg/day (–14.5% to –26.4%; P<0.05) linagliptin (both P<0.01). Liver fat content was significantly reduced by linagliptin in a dose-dependent manner (both doses P<0.001). Diet-induced obese mice treated for 4 weeks with 3 mg/kg/day or 30 mg/kg/day linagliptin had significantly improved glycated hemoglobin compared with vehicle (both P<0.001). Significant dose-dependent improvements in glucose disposal rates were observed during the steady state of the euglycemic–hyperinsulinemic clamp: 27.3 mg/kg/minute and 32.2 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 20.9 mg/kg/minute with vehicle (P<0.001). Hepatic glucose production was significantly suppressed during the clamp: 4.7 mg/kg/minute and 2.1 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 12.5 mg/kg/minute with vehicle (P<0.001). In addition, 30 mg/kg/day linagliptin treatment resulted in a significantly reduced number of macrophages infiltrating adipose tissue (P<0.05). Linagliptin treatment also decreased liver expression of PTP1B, SOCS3, SREBP1c, SCD-1 and FAS (P<0.05). Other tissues like muscle, heart and kidney were not significantly affected by the insulin sensitizing effect of linagliptin. Long-term linagliptin treatment reduced liver fat content in animals with diet-induced hepatic steatosis and insulin resistance, and may account for improved insulin sensitivity

GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation

Glucagon-like peptide-1 (GLP-1) promotes insulin secretion from pancreatic ß-cells in a glucose dependent manner. Several pathways mediate this action by rapid, kinase phosphorylation-dependent, but gene expression-independent mechanisms. Since GLP-1-induced insulin secretion requires glucose metabolism, we aimed to address the hypothesis that GLP-1 receptor (GLP-1R) signalling can modulate glucose uptake and utilization in ß-cells. We have assessed various metabolic parameters after short and long exposure of clonal BRIN-BD11 ß-cells and rodent islets to the GLP-1R agonist Exendin-4 (50 nM). Here we report for the first time that prolonged stimulation of the GLP-1R for 18 hours promotes metabolic reprogramming of ß-cells. This is evidenced by up-regulation of glycolytic enzyme expression, increased rates of glucose uptake and consumption, as well as augmented ATP content, insulin secretion and glycolytic flux after removal of Exendin-4. In our model, depletion of Hypoxia-Inducible Factor 1 alpha (HIF-1a) impaired the effects of Exendin-4 on glucose metabolism, while pharmacological inhibition of Phosphoinositide 3-kinase (PI3K) or mTOR completely abolished such effects. Considering the central role of glucose catabolism for stimulus-secretion coupling in ß-cells, our findings suggest that chronic GLP-1 actions on insulin secretion include elevated ß-cell glucose metabolism. Moreover, our data reveal novel aspects of GLP-1 stimulated insulin secretion involving de novo gene expression

Effect of a Dipeptidyl Peptidase-IV Inhibitor, Des-Fluoro-Sitagliptin, on Neointimal Formation after Balloon Injury in Rats

Background: Recently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms. Methods and Findings: Otsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-$\alpha$ and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs. Conclusions: Sitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes

Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer

Vascular endothelial growth factor (VEGF) receptors consist of three cell-membrane type receptors (VEGFR-1, VEGFR-2 and VEGFR-3), and soluble form of VEGFR-1 (sVEGFR-1), an intrinsic negative counterpart of the VEGF. In this study, we measured intratumoral protein levels of free and total VEGF, VEGFR-2 and sVEGFR-1 from 202 primary breast cancer tissues and examined their prognostic values. A significant inverse correlation was found between free or total VEGF and oestrogen receptor (ER) status (P=0.042 and 0.032, respectively). A univariate analysis showed that low sVEGFR-1 and high total VEGF were significantly associated with poor prognosis in disease-free survival (DFS) and overall survival (OS). The ratio of sVEGFR-1 to total VEGF was a strong prognostic indicator (DFS: P=0.008; OS: P=0.0002). A multivariate analysis confirmed the independent prognostic values of total VEGF and the ratio of sVEGFR-1 to total VEGF. In subgroup analysis, total VEGF was a significant prognostic indicator for ER-positive tumours but not for ER-negative tumours, whereas sVEGFR-1 was significant for ER-negative tumours but not for ER-positive tumours. In conclusion, the intratumoral sVEGFR-1 level, VEGF level and the ratio of sVEGFR-1 to total VEGF are potent prognostic indicators of primary breast cancer, and might be relevant to ER status